Latent TGF-β-binding protein 4 modifies muscular dystrophy in mice
Latent TGF-β-binding protein 4 modifies muscular dystrophy in mice
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DOI：
10.1172/jci39845
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发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
McNally, Elizabeth M.
中科院分区：
文献类型：
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作者：
Heydemann, Ahlke;Ceco, Ermelinda;McNally, Elizabeth M.
大多数单基因疾病，包括肌肉萎缩症，表现出不均匀的表型。出现表型变异的部分原因是由于存在增强或抑制疾病过程的遗传修饰因子。我们采用无偏定位的方法来寻找改变小鼠肌肉萎缩症的基因。在全基因组扫描中，我们在7号染色体上发现了一个影响肌肉萎缩症、肌膜通透性和肌肉纤维化两种病理特征的单一强位点。在这一基因组区间内，发现潜伏tgf - β结合蛋白4基因（Ltbp4）编码区存在36bp的插入/缺失多态性。Ltbp4编码一种潜在的tgf - β结合蛋白，该蛋白隔离tgf - β并调节其与tgf - β受体结合的可用性。在肌营养不良小鼠模型中，将12个氨基酸插入到LTBP4富含脯氨酸的区域可减少蛋白水解裂解，并与tgf - β信号传导减少、纤维化减少和肌肉病理改善有关。相反，LTBP4中12个氨基酸的缺失与蛋白水解、SMAD信号和纤维化增加有关。这些数据确定Ltbp4是调节tgf - β信号和改变肌营养不良预后的靶基因。
Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-beta-binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-beta-binding protein that sequesters TGF-beta and regulates its availability for binding to the TGF-beta receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-beta signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-beta signaling and modify outcomes in muscular dystrophy.